Proanthocyanidins (also known as procyanidin oligomeric proanthocyanidin (OPC) or condensed tannins) are ubiquitous in plants and are important constituents of the human diet. A wide range of potentially significant biological activities including antioxidant, anti-atherosclerotic, anti-inflammatory, antitumor, antiosteoporotic, and antiviral effects have been attributed to this class of compounds.
Proanthocyanidins are dimers, trimers, oligomers or polymers of flavanols. Flavanols (also referred to as flavan-3-ols) are a class of flavonoids and include (+)-catechin (compound 1) of Formula (A) and (−)-epicatechin (compound 2) of Formula (A). Compound 1 or compound 2, as monomer units, are linked via their 4- and 8-, or 4- and 6-positions to form proanthocyanidins. Progress in the chemistry and biology of these compounds has been slow due to the difficulty of isolating and synthesizing pure free phenolic compounds.

The production of proanthocyanidins and analogues thereof by the introduction of flavanyl, flavonoid and other phenolic moieties at C-4 of flavan-3,4-diols is known in the art and has been achieved by acid catalyzed condensation of the appropriate nucleophilic and electrophilic units. These initial stereoselective synthetic methods played an important role in the structure elucidation of the economically important profisetinidins and prorobinetinidins from Acacia mearnsii (Black Wattle) and Schinopsis spp up to the tetrameric level.
However, the above methods were hampered by the laborious extraction procedures required to obtain optically active starting materials that occur in low concentrations in plant material. Synthetic access to proanthocyanidin dimers, trimers, tetramers, higher oligomers and polymers as well as analogues thereof has been greatly enhanced by the introduction of a C-4 leaving group for purposes of increasing electrophilicity at the C-4 benzylic position of commercially available (+)-catechin (compound 1) and (−)-epicatechin (compound 2). The introduction of a C-4 leaving group thus requires the performance of an extra step in the synthesis, namely the preparation of what will herein be referred to as C-4 functionalised precursors. Further disadvantages associated therewith are discussed below.
The preparation of C-4 functionalised precursors is known in the art and is, amongst other methods, achieved by the selective bromination at C-4 of compounds 1 and 2. Bromination is only possible with peracetates where the reactivity of the aromatic rings towards competing bromination is suppressed by electron withdrawing acetate groups. However, in order to control the degree of polymerization, protection at C-8 of the electrophilic species prior to condensation was required.
Other methods, which involve the introduction of sulphur or oxygen at C-4, have also been reported and have been used as an intermediate step for introducing a flavanyl or phenolic moiety at C-4 of flavan-3-ols for the production of proanthocyanidins and analogues thereof.
A further disadvantage associated with the prior art methods discussed herein above resides in the undesirable self-condensation of the C-4-functionalized precursors. This self-condensation of the precursors with a leaving group on C-4 has a significant effect on the degree of polymerization. Accordingly, the degree of polymerization is difficult to control such that a complex mixture of dimers, trimers, tetramers and higher oligomers as well as a complex mixture of analogues is formed. It will be appreciated that each C-4 functionalized precursor contains an electrophilic centre, with the result that after C—C bond formation between said precursor and a nucleophile, one electrophilic and one nucleophilic centre are present that are capable of reacting further and disadvantageously the degree of polymerization cannot be controlled. Where the precursor and a nucleophile are identical, a complex mixture of dimers, trimers, tetramers and higher oligomers is undesirably formed whilst a complex mixture of analogues is undesirably formed in the case of a non-identical precursor and nucleophile. The present invention allows for improved control over the degree of polymerisation and the lessening of self-polymerisation.
Yet a further disadvantage of previously known methods for the synthetic preparation of proanthocyanidins and analogues thereof involving the introduction of leaving groups on the C-4 carbon of flavan-3-ols, such as catechin or epicatechin, is that the known processes generally favours the predominant formation of 3,4-trans isomers of proanthocyanidins with generally very low yields of the 3,4-cis isomers. The present invention, in contrast, allows for greatly improved yields of the 3,4-cis isomers.
The term “flavonoid” is used in this description and dependent claims in its wider meaning which includes the compounds also known as flavanoids.
In this specification, the term “proanthocyanidin” denotes a compound which is essentially a multimer of from two to twenty identical monomeric units having flavonoid base structures and which are bonded together in a chain of such units by carbon to carbon interflavanyl bonds between a carbon of an aromatic ring of one unit and the C-4 carbon of another unit. Thus the compound catechin-(4β→8)-catechin is an example of a proanthocyanidin according to the meaning which that term denotes in this description of the invention and appended claims.
The expression “proanthocyanidin analogue” as used herein denotes a compound which is essentially composed of one to twenty monomeric units having flavonoid base structures and which, if there is more than one unit having a flavonoid base are bonded together in a chain of such units by carbon to carbon interflavanyl bonds between a carbon of an aromatic ring of one unit and the C-4 carbon of another unit, but wherein at least some of the flavonoid base monomeric units are dissimilar in structure from the others, and wherein one or more of the units may be a non-flavonoid base unit or units, provided that such non-flavonoid unit or units includes a nucleophilic aromatic moiety, and a carbon of such nucleophilic aromatic moiety forms an carbon to carbon bond with the C-4 carbon of a flavonoid base unit. Thus the compound (2R,4R)-4-(1,3,5-tri-O-methylphloroglucinol)-5,7,3′4′-tetra-O-methyl-flavan-3-one is an example of a proanthocyanidin analogue within the meaning ascribed to that expression for purposes of the present description and appended claims in respect of the present invention.
Also in this specification, the terms “dimer” and “trimer” respectively denote an association of two and three identical constituent units linked together, and the terms, oligomer and polymer have corresponding meanings. The formation of a dimer in accordance with the method of the present invention accordingly results in a proanthocyanidin.
Further, in this specification, the term “adduct” denotes an association of two non-identical constituent units linked together by means of carbon to carbon bonds. The formation of an adduct in accordance with the method of the present invention results in a proanthocyanidin analogue.